Effect of netupitant, a highly selective NK₁ receptor antagonist, on the pharmacokinetics of midazolam, erythromycin, and dexamethasone.

Purpose: Netupitant is a new highly selective neurokinin-1 receptor antagonist being studied for the prevention of nausea and vomiting in patients undergoing chemotherapy. In vitro studies suggest that netupitant inhibits the cytochrome P-450 isoenzyme 3A4 (CYP3A4). Because netupitant may be used with a variety of drugs, which may be substrates of CYP3A4, two studies were designed to establish the potential risk for drug-drug interaction with three different CYP3A4 substrates: midazolam, erythromycin, and dexamethasone.

Methods: Both trials were three-period crossover studies performed in healthy subjects. In the first study, 20 subjects received netupitant and either midazolam or erythromycin. In the second study, 25 subjects received netupitant and dexamethasone. Serial blood samples were collected over the course of the two studies and pharmacokinetic parameters were determined for all analytes.

Results: Netupitant, by inhibiting the CYP3A4, increased the C max and AUCinf of midazolam by 40 and 144 %, respectively, and the C max and AUCinf of erythromycin by 30 %. Netupitant was shown to increase the exposure to dexamethasone in a dose-dependent manner with the mean increase in AUC and C max by 72 and 11 %, respectively, on day 1 and by 138 and 75 %, respectively, on day 4 when co-administered with 300 mg of netupitant.

Conclusions: The results of these studies suggest that netupitant is a moderate inhibitor of CYP3A4 and therefore, co-administration with drugs that are substrates of CYP3A4 may require dose adjustments. Treatments were well tolerated in both studies.